الفهرس 
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Abstract
Acute myeloid leukemia is a clinically and biologically heterogeneous disease characterized by development of a malignant clone of myeloid cells in the bone marrow with arrest of maturation at blast level that accumulates and dominates on the normal bone marrow activity leading to marrow failure.
In spite of remarkably improved cure rate in AML over the past decade, recurrent or refractory leukemia remains the major problem of the AML and no clearly effective therapy has been established so far. Traditional treatments such as chemotherapy and hematopoietic stem cell transplantation are still not satisfactory for the patients. Besides, conventional treatments usually have many side effects to result in poor prognosis. Therefore, an urgent need is necessary to update therapies of AML.
Mammalian target of rapamycin (mTOR) is a 289 kDa serine/threonine kinase belonging to the PI3K-related protein kinase (PIKKs) family since its C-terminus shares strong homology to the catalytic domain of PIK3. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling.
mTOR is an important downstream effector of PI3K/AKT and LKB1/AMPK pathway, that play critical roles in hematopoiesis. Thus Therapeutic interference of mTOR and its related pathway has become an attractive strategy in hematological malignancies especially AML therapies .
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The present study was designed to evaluate mTOR gene expression as one of intracellular signaling proteins and to assess its relation to clinical characteristics in newly diagnosed AML patients and hence its implications in determining the prognosis.
Our study included 50 newly diagnosed AML patients (33males and 17 females) aged between 16 and 73 years.
All patients were subjected to the following:
I) Clinical Assessment:
History:
Clinical Examination.
II) Laboratory Investigations:
A. Routine work-up of leukemia patients:
Laboratory data were reviewed from patients’ medical records to establish the diagnosis and classification and included:
Complete blood counts,
Bone marrow examination,
Cytochemistry,
Immunophenotyping,
Cytogenetics and
Molecular detection for FLT3.
B. Special Investigations:
Detection of expression levels of mTOR gene by SYBR Green Real time PCR in AML bone marrow samples.
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Detection of expression levels of mTOR gene by SYBR Green Real time PCR also was done in 10 additional samples of morphologically normal bone marrow and the mean of their mTOR gene expression was used as the normal calibrator of our results.
Statistical analysis was done between mTOR and different parameters and showed the following results:
mTOR expression and patients characteristics:
No statistical significant difference in mTOR expression among different age groups, between males and females or among different FAB subtypes, p = 0.799, 0.349 and 0.261 respectively. However, Patients with acute promyelocytic leukemia had significantly lower mTOR mRNA compared to other FAB subtypes, p = 0.035.
No statistical significance difference in mTOR expression between patients with lymphadenopathy, splenomegaly and/or hepatomegaly and those who with no organomegaly at presentation. (p=0.276, p=0.649, p= 0.332 and 0.704).
Positive correlation between mTOR mRNA levels and bone marrow blast count, r = 0.285, p = 0.045. However, this correlation was not demonstrated between mTOR expression and HB level, TLC, platelets count or peripheral blasts.
Statistically significant difference in mTOR expression among the different risk groups being highest in the poor risk (18.64 ± 19.44) compared to the intermediate risk (6.05± 5.04) and the favorable risk groups (3.85 ± 2.44, p = 0.011).
Statistically significant higher mTOR expression in the poor risk group compared to the favorable risk (p = 0.001) and intermediate risk (p = 0.02)
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but no significant difference between the favorable and intermediate risk was seen (p = 0.068).
Statistically significant higher mTOR mRNA levels in the patients harboring mutant FLT3 compared to those carrying the wild gene (p = 0.003).
mTOR expression in relation to disease outcome:
Statistically significant higher mTOR expression in the patients who did not achieve CR than those who were in CR after initial chemotherapy, p<0.001.
Statistically significant higher levels in the non CR group compared to the CR in both intermediate (p= 0.002) and poor risk groups (p 0.003).
No significant difference in mTOR expression was seen between responders and non-responders in the favorable risk category.
Significantly higher levels of expression were seen in those who failed to achieve CR compared to those who were in CR in each of the subgroup with normal karyotype , Wild and mutant FLT-3.
Receiver Operator characteristic (ROC) curve shows that mTOR at cutoff level (5.2) can significantly detect patient response to chemotherapy at day 28 with a sensitivity of 76 %, specificity of 80%, negative predictive value of 79.2 % and positive predictive value of 76.9 %.
Mean overall survival of 12.0 months in the CR group compared to 2.6 months for the non-CR group, p < 0.001, with an overall survival of 61% and less than 10% at 12 months follow up respectively.
Statistically significant negative correlation between OS and mTOR level in both CR (r=- 0.531 and p= 0.019) and non CR(r= - 0.437and p=0.016) groups while no correlation is observed between mTOR level and DFS in CR (r=-0.43 and p=0.075) and non CR(r=- 0.207and p=0.396)